伊马替尼减轻DOCA诱导的大鼠心肌纤维化与PDGFs/PDGFRs信号通路有关  

Imatinib attenuates DOCA/salt-induced rat myocardial fibrosis via PDGFs/PDGFRs signaling pathway

作　　者：范彬[1] 马礼坤[1] 李谦[1] 汪麟[1] 周俊岭[1] 吴佳纬 

机构地区：[1]安徽医科大学附属省立医院心血管内科,安徽合肥230001

出　　处：《中国病理生理杂志》2014年第3期430-437,共8页Chinese Journal of Pathophysiology

基　　金：安徽省国际合作计划项目(No.09080703042)

摘　　要：目的:探讨血小板源性生长因子(PDGFs)/PDGF受体(PDGFRs)信号通路拮抗剂伊马替尼(IMA)减轻醋酸去氧皮质酮(DOCA)诱导的盐敏感性高血压大鼠心肌纤维化的作用机制及PDGFs/PDGFRs信号通路在其中的作用。方法:60只雄性SD大鼠行右肾切除术,术后予以1%氯化钠和0.1%氯化钾饮水4周并随机分成3组:对照组、实验组(DOCA组)和治疗组(DOCA+IMA组)。使用尾套法每2周测定1次大鼠动脉收缩压(SBP),苦味酸-天狼星红染色观察大鼠心肌间质纤维化程度和心肌血管周围胶原面积(PVCA)/血管腔面积(VA)比值,实时荧光定量PCR法检测心肌组织成纤维细胞特异蛋白1(FSP-1)、α-平滑肌肌动蛋白(α-SMA)、前胶原蛋白Ⅰ(procollagenⅠ)、前胶原蛋白Ⅲ(procollagenⅢ)、PDGFRα和PDGFRβ的mRNA含量,免疫组化法观察心肌组织波形蛋白(vimentin)、α-SMA、PDGFRα、PDGFRβ及磷酸化的PDGFRβ(p-PDGFRβ)的蛋白表达,免疫荧光法定位PDGFRα和PDGFRβ表达的细胞类型。结果:(1)干预第14天和第28天血压测定结果显示DOCA及DOCA+IMA组大鼠的SBP均明显高于对照组(P<0.01),而DOCA组与DOCA+IMA组的SBP无显著差异(P>0.05)。干预第28天,DOCA组心肌间质纤维化程度和PVCA/VA比值明显高于对照组(P<0.01),DOCA+IMA组心肌间质纤维化程度和PVCA/VA比值虽高于对照组(P<0.05),但较DOCA组显著减小(P<0.01)。(2)干预第14天,DOCA组的PDGFRα和PDGFRβ表达较对照组增加(P<0.01),DOCA+IMA组的PDGFRα和PDGFRβ表达较DOCA组减少(P<0.01)。干预第28天,与对照组相比,DOCA组的PDGFRβ、p-PDGFRβ、FSP-1、α-SMA、procollagenⅠ和procollagenⅢ表达明显增加(P<0.01),而PDGFRα的表达未见明显增加,组内比较显示PDGFRβ表达大于PDGFRα,DOCA+IMA组PDGFRβ、p-PDGFRβ、FSP-1、α-SMA、procollagenⅠ和procollagenⅢ表达较DOCA组减少(P<0.01)。(3)干预第28天,对照组大鼠心脏间质主要是vimentin阳性的成纤维细胞,α-SMA表达很少,DOCA组大鼠α-SMA阳性的梭形细胞(�AIM： To investigate the role of imatinib （IMA） in reducing myocardial fibrosis and its relationship with platelet-derived growth factors （PDGFs）/PDGF receptors （PDGFRs） signaling pathway in deoxycorticosterone acetate （DOCA）/salt-induced hypertension in rats. METHODS： Sixty male uninephrectomized SD rats were treated with 1%NaC1 and 0.2% KC1 in the drinking water for 4 weeks and randomly divided into vehicle control （CON） group, DOCA treatment （DOCA） group and DOCA plus IMA treatment （ DOCA ＋ IMA） group. Systolic blood pressure （SBP） was mea sured weekly using the tail-cuff method. The extent of myocardial interstitial fibrosis and the ratio of perivascular collagen area/vascular area （PVCA/VA） were analyzed by picro-Sirius red staining. The mRNA expression of fibroblast-specific protein 1 （ FSP-1 ）, a-smooth muscle actin （et-SMA） , proeollagen I , procollagenlll, PDGFRct and PDGFRI3 in the myo eardium was measured by real-time PCR. The protein levels of PDGFRa, PDGFRI3, p-PDGFRI3, vimentin and α-SMA were analyzed by immunohistochemical staining. The cell types of PDGFRct and PDGFRI3 loealizations were examined by immunofluoreseence method. RESULTS ： （ 1 ） SBP in DOCA and DOCA ＋ IMA groups was higher than that in CON group on day 14 and day 28, and no difference of SBP between DOCA group and DOCA ＋ IMA group was found. The extent of myocardial interstitial fibrosis and the ratio of PVCA/VA in DCOA group were higher than those in CON group, and those in DOCA ＋ IMA group were significantly lower than those in DOCA group on day 28. （2） Compared with CON group, the expression of PDGFRct and PDGFRI3 in DOCA group was increased on day 14. Compared with DOCA group, the expres sion of PDGFRet and PDGFRI3 in DOCA ＋ IMA group was attenuated. Compared with CON group, the expression of PDGFRI3, p-PDGFRI3, FSP-1, ot-SMA, procollagen I and procollagen llI in DOCA group was increased significantly on day 28, but the expression of PDGFRct was not increased sign

关 键 词：伊马替尼 受体 血小板源性生长因子 心肌成纤维细胞 心肌纤维化 

分 类 号：R542.23[医药卫生—心血管疾病] R329.21[医药卫生—内科学]